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Molecular and Cellular Biology, January 2002, p. 257-269, Vol. 22, No. 1
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.1.257-269.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

v-Src-Induced Modulation of the Calpain-Calpastatin Proteolytic System Regulates Transformation

The Beatson Institute for Cancer Research, Cancer Research Campaign Beatson Laboratories, Glasgow G61 1BD,¹ Institute of Biological and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom,⁴ Department of Medicine, Division of Hematology/Oncology, Department of Biochemistry and Molecular Biology, and Walther Oncology Center, Indiana University, Indianapolis, Indiana,² Cancer Research Laboratories, Department of Biochemistry, Queen’s University, Kingston, Ontario K7L 3N6, Canada³

Received 3 May 2001/ Returned for modification 2 July 2001/ Accepted 2 October 2001

v-Src-induced oncogenic transformation is characterized by alterations in cell morphology, adhesion, motility, survival, and proliferation. To further elucidate some of the signaling pathways downstream of v-Src that are responsible for the transformed cell phenotype, we have investigated the role that the calpain-calpastatin proteolytic system plays during oncogenic transformation induced by v-Src. We recently reported that v-Src-induced transformation of chicken embryo fibroblasts is accompanied by calpain-mediated proteolytic cleavage of the focal adhesion kinase (FAK) and disassembly of the focal adhesion complex. In this study we have characterized a positive feedback loop whereby activation of v-Src increases protein synthesis of calpain II, resulting in degradation of its endogenous inhibitor calpastatin. Reconstitution of calpastatin levels by overexpression of exogenous calpastatin suppresses proteolytic cleavage of FAK, morphological transformation, and anchorage-independent growth. Furthermore, calpastatin overexpression represses progression of v-Src-transformed cells through the G₁ stage of the cell cycle, which correlates with decreased pRb phosphorylation and decreased levels of cyclins A and D and cyclin-dependent kinase 2. Calpain 4 knockout fibroblasts also exhibit impaired v-Src-induced morphological transformation and anchorage-independent growth. Thus, modulation of the calpain-calpastatin proteolytic system plays an important role in focal adhesion disassembly, morphological transformation, and cell cycle progression during v-Src-induced cell transformation.

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